This invention relates to a new and useful process for preparing a ketone enantiomer. More particularly, it is concerned with a novel multi-step process for preparing the (4S)-enantiomer of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone in a highly optically-pure form. The latter compound, which is a novel (4S)-enantiomer per se, has utility as a key intermediate that ultimately leads to the production of pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro1-naphthale neamine (sertraline), which is a known antidepressant agent. The invention also includes within its scope certain other novel compounds which are useful as intermediates in the various stages of the overall process.
There is described in U.S. Pat. Nos. 4,536,518 and 4,556,676 to W. M. Welch, Jr. et al., as well as in the paper of W. M. Welch, Jr. et al., appearing in the Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984), a multi-step method for synthesizing pure racemic cis(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthale neamine, starting from the readily available 3,4-dichlorobenzophenone and proceeding via the known racemic or (.+-.)-4-(3,4-dichlorophenyl)-4-butanoic acid and then to (.+-.)-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone (see also U.S. Pat. Nos. 4,777,288 and 4,839,104 to G. J. Quallich et al. for improved methods leading to these intermediates), with the latter ketone then being condensed with methylamine in the presence of titanium tetrachloride to yield N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methenamine. In the last step of the overall synthesis, the aforementioned imine is then readily reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to yield N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine, which is actually a mixture of the cis- and trans-isomers in the form of a racemate. The aforesaid isomeric mixture is then separated into its component parts by conventional means, e.g., by fractional crystallization of the hydrochloride salts or by column chromatography on silica gel of the corresponding free base. Resolution of the separated cis-racemate free base compound while in solution with an optically-active selective precipitant acid, such as D-(-)-mandelic acid, then ultimately affords the desired cis(1S)(4S)-enantiomer (sertraline).
Nevertheless, the above described production of pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal eneamine (sertraline) is disadvantageous in that equal amounts of the unwanted cis(1R)(4R)-enantiomer are co-produced and must eventually be discarded, thereby lowering the overall yield of the desired cis-(1S)(4S)-enantiomer and increasing the total costs of production.
Other asymmetric methods of induction (e.g., asymmetric synthesis) have been employed in the past with variable success in the field of organo-metallic chemistry to stereoselectively convert (and thereby resolve) other specific substrates. For instance, in a paper by T. Mukaiyama et al., appearing in Chemistry Letters, p. 913 (1981), there is described the Michael addition of various Grignard reagents, such as n-butylmagnesium bromide, to certain chiral .alpha.,.beta.-unsaturated carboxylic acid amides that are derived from L-(-)-ephedrine (e.g., the corresponding crotonic acid amide) to yield the corresponding highly optically-active .beta.-substituted alkanoic acids, like (S)-3-methylheptanoic acid, after acid hydrolysis. In those instances where an aromatic Grignard reagent, such as phenylmagnesium bromide, was employed as the reagent, the corresponding chiral product obtained (i.e., the highly optically-active .beta.-substituted phenylpropionic acid) always appeared to be of the (S)-configuration.